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Entry
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- #603284 - CEREBRAL CAVERNOUS MALFORMATIONS 2; CCM2
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- OMIM
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<p>
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<span class="h4">#603284</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/603284"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS116860"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#mapping">Mapping</a>
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<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<span class="panel-title">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div><a href="https://clinicaltrials.gov/search?cond=CEREBRAL CAVERNOUS MALFORMATIONS" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=18935&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1293/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/7938" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603284[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=221061" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060670" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/603284" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 221061<br />
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<strong>DO:</strong> 0060670<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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603284
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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CEREBRAL CAVERNOUS MALFORMATIONS 2; CCM2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/7/243?start=-3&limit=10&highlight=243">
|
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7p13
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Cerebral cavernous malformations-2
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/603284"> 603284 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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CCM2
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/607929"> 607929 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/603284" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS116860" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/603284" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/603284" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> SKIN, NAILS, & HAIR </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
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<em> Skin </em>
|
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</span>
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</div>
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
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|
|
- Palmar telangiectases (described in 1 family) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747193&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747193</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<strong> NEUROLOGIC </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
|
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|
|
- Cerebral cavernous malformations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/444869007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">444869007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2919945&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2919945</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033522" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033522</a>]</span><br /> -
|
|
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
|
|
Recurrent headaches <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/712826000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">712826000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239888</a>, <a href="https://bioportal.bioontology.org/search?q=C1168188&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1168188</a>]</span><br /> -
|
|
Hemorrhagic stroke <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5234922&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5234922</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001342" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001342</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001342" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001342</a>]</span><br />
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|
|
</span>
|
|
</div>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Genetic heterogeneity (see <a href="/entry/116800">116800</a> for summary) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242960</a>]</span><br /> -
|
|
Sporadic cases often single lesions versus multiple lesions in familial cases<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
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|
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</div>
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the CCM2 scaffold protein gene (CCM2, <a href="/entry/607929#0001">607929.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
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|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Cerebral cavernous malformations
|
|
- <a href="/phenotypicSeries/PS116860">PS116860</a>
|
|
- 7 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/842?start=-3&limit=10&highlight=842"> 3q26.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603285"> Cerebral cavernous malformations-3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603285"> 603285 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609118"> PDCD10 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609118"> 609118 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/876?start=-3&limit=10&highlight=876"> 3q26.32 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619538"> Cerebral cavernous malformations 4, somatic </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619538"> 619538 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/171834"> PIK3CA </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/171834"> 171834 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/243?start=-3&limit=10&highlight=243"> 7p13 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603284"> Cerebral cavernous malformations-2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603284"> 603284 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607929"> CCM2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607929"> 607929 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/406?start=-3&limit=10&highlight=406"> 7q21.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/116860"> Cavernous malformations of CNS and retina </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/116860"> 116860 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604214"> KRIT1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604214"> 604214 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/406?start=-3&limit=10&highlight=406"> 7q21.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/116860"> Cerebral cavernous malformations-1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
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<p>A number sign (#) is used with this entry because of evidence that cerebral cavernous malformations-2 (CCM2) is caused by heterozygous mutation in the CCM2 gene (<a href="/entry/607929">607929</a>) on chromosome 7p13.</p><p>Evidence suggests that a 2-hit mechanism involving biallelic germline and somatic mutations is responsible for CCM2 pathogenesis; see PATHOGENESIS and MOLECULAR GENETICS sections.</p>
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<p>Cerebral cavernous malformations are vascular malformations, mostly located within the CNS, characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. CCMs usually present clinically during the third to fifth decade of life, resulting in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits (summary by <a href="#5" class="mim-tip-reference" title="Denier, C., Goutagny, S., Labauge, P., Krivosic, V., Arnoult, M., Cousin, A., Benabid, A. L., Comoy, J., Frerebeau, P., Gilbert, B., Houtteville, J. P., Jan, M., and 14 others. <strong>Mutations within the MGC4607 gene cause cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 74: 326-337, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14740320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14740320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14740320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/381718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14740320">Denier et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14740320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (<a href="/entry/116860">116860</a>).</p>
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<p><a href="#1" class="mim-tip-reference" title="Ahdab, R., Riant, F., Brugieres, P., Roujeau, J.-C., Hodel, J., Hosseini, H. <strong>Familial cerebral cavernomatous malformations associated with palmar capillary telangiectasias.</strong> Neurology 71: 861-862, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18779516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18779516</a>] [<a href="https://doi.org/10.1212/01.wnl.0000325474.61048.ae" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18779516">Ahdab et al. (2008)</a> reported 2 sibs with CCM2 confirmed by genetic analysis. The 57-year-old proband presented with generalized tonic-clonic seizures and status epilepticus. Brain MRI showed multiple rounded gradient echo hypointense signals mainly in the right frontotemporal region, consistent with CCM. He also had numerous small erythematous 2 to 3-mm macules that blanched on his palms. The pattern was consistent with capillary telangiectasia. His 60-year-old sister developed mild gait ataxia associated with multiple supra- and infratentorial CCMs on brain MRI. She also had palmar telangiectasia. Their mother reportedly had episodes of diplopia and vertigo and also had the same palmar lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18779516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For each of the 3 CCM genes, <a href="#12" class="mim-tip-reference" title="Pagenstecher, A., Stahl, S., Sure, U., Felbor, U. <strong>A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.</strong> Hum. Molec. Genet. 18: 911-918, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088124">Pagenstecher et al. (2009)</a> showed complete localized loss of either KRIT1 (<a href="/entry/604214">604214</a>), CCM2/malcavernin, or PDCD10 (<a href="/entry/609118">609118</a>) protein expression depending on the respective inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein, but stained positively for the 2 other proteins. Immunohistochemical studies demonstrated endothelial cell mosaicism as neoangiogenic vessels within caverns from a CCM1 patient and normal brain endothelium from a CCM2 patient stained positively for KRIT1 and CCM2/malcavernin, respectively. <a href="#12" class="mim-tip-reference" title="Pagenstecher, A., Stahl, S., Sure, U., Felbor, U. <strong>A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.</strong> Hum. Molec. Genet. 18: 911-918, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088124">Pagenstecher et al. (2009)</a> suggested that complete lack of CCM protein in affected endothelial cells from CCM germline mutation carriers supports a 2-hit mechanism for CCM formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19088124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Craig, H. D., Gunel, M., Cepeda, O., Johnson, E. W., Ptacek, L., Steinberg, G. K., Ogilvy, C. S., Berg, M. J., Crawford, S. C., Scott, R. M., Steichen-Gersdorf, E., Sabroe, R., Kennedy, C. T. C., Mettler, G., Beis, M. J., Fryer, A., Awad, I. A., Lifton, R. P. <strong>Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27.</strong> Hum. Molec. Genet. 7: 1851-1858, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811928</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811928">Craig et al. (1998)</a> reported analysis of linkage in 20 non-Hispanic Caucasian kindreds with familial CCM. Linkage to new loci, CCM2 at 7p15-p13 and CCM3 (<a href="/entry/603285">603285</a>) at 3q25.2-q27, was demonstrated. Multilocus analysis yielded a maximum lod score of 14.11, with 14% of kindreds linked to CCM1, 20% linked to CCM2, and 40% linked to CCM3, with highly significant evidence for linkage to 3 loci; linkage to 3 loci was supported with an odds ratio of 2.6 x 10(5):1 over linkage to 2 loci, and 1.6 x 10(9):1 over linkage to 1 locus. Multipoint analysis among families with high posterior probabilities of linkage to each of the 3 loci refined the locations of CCM2 and CCM3 to approximately 22 cM intervals. Linkage to these 3 loci can account for inheritance of CCM in all kindreds studied. Significant locus-specific differences in penetrance were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9811928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of CCM2 in the families reported by <a href="#9" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> sequenced positional candidate genes in the 7p region for mutations in CCM2. One of these genes, the CCM2 gene, which they called MGC4607, was chosen because its translation product protein encodes a putative phosphotyrosine-binding (PTB) domain. The same domain is found in ICAP1-alpha (<a href="/entry/607153">607153</a>), a binding partner of the KRIT1 gene (<a href="/entry/604214">604214</a>). In a panel of 27 probands without a KRIT1 mutation, <a href="#9" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> detected 8 different heterozygous mutations in the CCM2 gene (see, e.g., <a href="/entry/607929#0001">607929.0001</a>-<a href="/entry/607929#0004">607929.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 (14%) of 14 unrelated patients with sporadic CCM and multiple lesions, <a href="#6" class="mim-tip-reference" title="Felbor, U., Gaetzner, S., Verlaan, D. J., Vijzelaar, R., Rouleau, G. A., Siegel, A. M. <strong>Large germline deletions and duplication in isolated cerebral cavernous malformation patients.</strong> Neurogenetics 8: 149-153, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17211633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17211633</a>] [<a href="https://doi.org/10.1007/s10048-006-0076-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17211633">Felbor et al. (2007)</a> identified a respective deletion in the CCM2 gene using multiplex ligation-dependent probe amplification. One of the deletions involved the entire coding region of the CCM2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17211633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 8 (13%) of 63 U.S. families with CCM, <a href="#10" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Squitieri, F., Leedom, T. P., Ptacek, L., Johnson, E. W., Marchuk, D. A. <strong>Deletions in CCM2 are a common cause of cervical cavernous malformations.</strong> Am. J. Hum. Genet. 80: 69-75, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160895">Liquori et al. (2007)</a> identified a 77.6-kb deletion encompassing exons 2 through 10 in the CCM2 gene (<a href="/entry/607929#0009">607929.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17160895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Liquori, C. L., Penco, S., Gault, J., Leedom, T. P., Tassi, L., Esposito, T., Awad, I. A., Frati, L., Johnson, E. W., Squitieri, F., Marchuk, D. A., Gianfrancesco, F. <strong>Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts.</strong> Neurogenetics 9: 25-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18060436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18060436</a>] [<a href="https://doi.org/10.1007/s10048-007-0109-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18060436">Liquori et al. (2008)</a> reported 6 additional CCM families from the United States with the 77.6-kb CCM2 deletion. Haplotype analysis, which included the previously reported families with this deletion, indicated a founder effect. This deletion was not present in 24 Italian families with CCM, indicating that it is specific to a certain cohort of patients. Among the 24 Italian families with CCM, <a href="#11" class="mim-tip-reference" title="Liquori, C. L., Penco, S., Gault, J., Leedom, T. P., Tassi, L., Esposito, T., Awad, I. A., Frati, L., Johnson, E. W., Squitieri, F., Marchuk, D. A., Gianfrancesco, F. <strong>Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts.</strong> Neurogenetics 9: 25-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18060436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18060436</a>] [<a href="https://doi.org/10.1007/s10048-007-0109-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18060436">Liquori et al. (2008)</a> identified 4 deletions and 1 duplication in the CCM2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18060436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By use of repeated cycles of amplification, subcloning, and sequencing of multiple clones per amplicon, <a href="#2" class="mim-tip-reference" title="Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A. <strong>Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.</strong> Hum. Molec. Genet. 18: 919-930, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088123">Akers et al. (2009)</a> identified somatic mutations that were otherwise invisible by direct sequencing of the bulk amplicon. Biallelic germline and somatic mutations were identified in CCM lesions from all 3 forms of inherited CCMs. The somatic mutations were found only in a subset of the endothelial cells lining the cavernous vessels and not in interstitial lesion cells. Although widely expressed in the different cell types of the brain, the authors also suggested a unique role for the CCM proteins in endothelial cell biology. <a href="#2" class="mim-tip-reference" title="Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A. <strong>Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.</strong> Hum. Molec. Genet. 18: 919-930, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088123">Akers et al. (2009)</a> suggested that CCM lesion genesis may require complete loss of function for one of the CCM genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19088123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Gallione, C. J., Solatycki, A., Awad, I. A., Weber, J. L., Marchuk, D. A. <strong>A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.</strong> Genet. Med. 13: 662-666, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21543988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21543988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21543988[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1097/GIM.0b013e318211ff8b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21543988">Gallione et al. (2011)</a> identified a founder mutation in the Ashkenazi Jewish population that affects mRNA splicing of the CCM2 gene causing cerebral cavernous malformations (<a href="/entry/607929#0010">607929.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21543988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 27 unrelated patients with CCM and heterozygosity for the 77.6-kb deletion (<a href="/entry/607929#0009">607929.0009</a>) encompassing exons 2-10 of the CCM2 gene, <a href="#7" class="mim-tip-reference" title="Gallione, C. J., Detter, M. R., Sheline, A., Christmas, H. M., Lee, C., Marchuk, D. A. <strong>Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene.</strong> Hum. Genet. 141: 1761-1769, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35488064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35488064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35488064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00439-022-02458-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35488064">Gallione et al. (2022)</a> sequenced 10 kb upstream and downstream of the deletion to evaluate for a shared haplotype. SNP analysis demonstrated a shared haplotype among all 27 patients. The deletion was shown to be due to a recombination between an AluSx and an AluSg sequence, which, although highly homologous, are not identical. Genealogy studies showed that 5 of the families may share a single common ancestor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35488064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F. <strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong> J. Med. Genet. 57: 400-404, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31937560">Bergametti et al. (2020)</a> identified 6 heterozygous mutations in the CCM2 gene (<a href="/entry/607929#0007">607929.0007</a>; <a href="/entry/607929#0011">607929.0011</a>-<a href="/entry/607929#0015">607929.0015</a>) in 7 unrelated patients with CCM. The mutations were identified by sequencing of 3 genes associated with cerebral cavernous malformations. Coimmunoprecipitation studies with each of the mutations resulted in loss of interaction between CCM1 and CCM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1212/01.wnl.0000325474.61048.ae" target="_blank">Full Text</a>]
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Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A.
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<strong>Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.</strong>
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Hum. Molec. Genet. 18: 919-930, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19088123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F.
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<strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong>
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J. Med. Genet. 57: 400-404, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14740320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14740320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14740320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14740320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/381718" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Felbor2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Felbor, U., Gaetzner, S., Verlaan, D. J., Vijzelaar, R., Rouleau, G. A., Siegel, A. M.
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<strong>Large germline deletions and duplication in isolated cerebral cavernous malformation patients.</strong>
|
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Neurogenetics 8: 149-153, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17211633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17211633</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17211633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-006-0076-7" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Gallione2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gallione, C. J., Detter, M. R., Sheline, A., Christmas, H. M., Lee, C., Marchuk, D. A.
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<strong>Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene.</strong>
|
|
Hum. Genet. 141: 1761-1769, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35488064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35488064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35488064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35488064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-022-02458-5" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Gallione2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gallione, C. J., Solatycki, A., Awad, I. A., Weber, J. L., Marchuk, D. A.
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<strong>A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.</strong>
|
|
Genet. Med. 13: 662-666, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21543988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21543988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21543988[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21543988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1097/GIM.0b013e318211ff8b" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Liquori2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A.
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<strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong>
|
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Am. J. Hum. Genet. 73: 1459-1464, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/380314" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Liquori2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Liquori, C. L., Berg, M. J., Squitieri, F., Leedom, T. P., Ptacek, L., Johnson, E. W., Marchuk, D. A.
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<strong>Deletions in CCM2 are a common cause of cervical cavernous malformations.</strong>
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Am. J. Hum. Genet. 80: 69-75, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17160895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/510439" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Liquori2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Liquori, C. L., Penco, S., Gault, J., Leedom, T. P., Tassi, L., Esposito, T., Awad, I. A., Frati, L., Johnson, E. W., Squitieri, F., Marchuk, D. A., Gianfrancesco, F.
|
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<strong>Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts.</strong>
|
|
Neurogenetics 9: 25-31, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18060436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18060436</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18060436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-007-0109-x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Pagenstecher2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pagenstecher, A., Stahl, S., Sure, U., Felbor, U.
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<strong>A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.</strong>
|
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Hum. Molec. Genet. 18: 911-918, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19088124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn420" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/04/2023
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 8/19/2011<br>George E. Tiller - updated : 8/26/2009<br>Cassandra L. Kniffin - updated : 3/23/2009<br>Cassandra L. Kniffin - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 5/4/2007<br>Victor A. McKusick - updated : 12/18/2003
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</span>
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</div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 11/13/1998
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/07/2023
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/04/2023<br>carol : 06/08/2023<br>carol : 03/10/2021<br>alopez : 08/24/2011<br>terry : 8/19/2011<br>wwang : 9/21/2010<br>wwang : 8/26/2009<br>wwang : 4/8/2009<br>ckniffin : 3/23/2009<br>wwang : 4/15/2008<br>ckniffin : 3/18/2008<br>wwang : 5/11/2007<br>ckniffin : 5/4/2007<br>wwang : 4/12/2006<br>cwells : 12/22/2003<br>terry : 12/18/2003<br>alopez : 10/1/1999<br>carol : 1/13/1999<br>carol : 11/13/1998
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</span>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 603284
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<h3>
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<span class="mim-font">
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CEREBRAL CAVERNOUS MALFORMATIONS 2; CCM2
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<strong>ORPHA:</strong> 221061;
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<strong>DO:</strong> 0060670;
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</span>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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Phenotype
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<th>
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Phenotype <br /> MIM number
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<th>
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Inheritance
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<th>
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Phenotype <br /> mapping key
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Gene/Locus
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<th>
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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7p13
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<td>
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<span class="mim-font">
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Cerebral cavernous malformations-2
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</td>
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<td>
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<span class="mim-font">
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603284
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<td>
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<td>
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<span class="mim-font">
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CCM2
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</td>
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<td>
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<span class="mim-font">
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607929
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that cerebral cavernous malformations-2 (CCM2) is caused by heterozygous mutation in the CCM2 gene (607929) on chromosome 7p13.</p><p>Evidence suggests that a 2-hit mechanism involving biallelic germline and somatic mutations is responsible for CCM2 pathogenesis; see PATHOGENESIS and MOLECULAR GENETICS sections.</p>
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<span class="mim-text-font">
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<p>Cerebral cavernous malformations are vascular malformations, mostly located within the CNS, characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. CCMs usually present clinically during the third to fifth decade of life, resulting in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits (summary by Denier et al., 2004). </p><p>For a discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (116860).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<strong>Clinical Features</strong>
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<p>Ahdab et al. (2008) reported 2 sibs with CCM2 confirmed by genetic analysis. The 57-year-old proband presented with generalized tonic-clonic seizures and status epilepticus. Brain MRI showed multiple rounded gradient echo hypointense signals mainly in the right frontotemporal region, consistent with CCM. He also had numerous small erythematous 2 to 3-mm macules that blanched on his palms. The pattern was consistent with capillary telangiectasia. His 60-year-old sister developed mild gait ataxia associated with multiple supra- and infratentorial CCMs on brain MRI. She also had palmar telangiectasia. Their mother reportedly had episodes of diplopia and vertigo and also had the same palmar lesions. </p>
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<strong>Pathogenesis</strong>
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<p>For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete localized loss of either KRIT1 (604214), CCM2/malcavernin, or PDCD10 (609118) protein expression depending on the respective inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein, but stained positively for the 2 other proteins. Immunohistochemical studies demonstrated endothelial cell mosaicism as neoangiogenic vessels within caverns from a CCM1 patient and normal brain endothelium from a CCM2 patient stained positively for KRIT1 and CCM2/malcavernin, respectively. Pagenstecher et al. (2009) suggested that complete lack of CCM protein in affected endothelial cells from CCM germline mutation carriers supports a 2-hit mechanism for CCM formation. </p>
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<strong>Mapping</strong>
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<p>Craig et al. (1998) reported analysis of linkage in 20 non-Hispanic Caucasian kindreds with familial CCM. Linkage to new loci, CCM2 at 7p15-p13 and CCM3 (603285) at 3q25.2-q27, was demonstrated. Multilocus analysis yielded a maximum lod score of 14.11, with 14% of kindreds linked to CCM1, 20% linked to CCM2, and 40% linked to CCM3, with highly significant evidence for linkage to 3 loci; linkage to 3 loci was supported with an odds ratio of 2.6 x 10(5):1 over linkage to 2 loci, and 1.6 x 10(9):1 over linkage to 1 locus. Multipoint analysis among families with high posterior probabilities of linkage to each of the 3 loci refined the locations of CCM2 and CCM3 to approximately 22 cM intervals. Linkage to these 3 loci can account for inheritance of CCM in all kindreds studied. Significant locus-specific differences in penetrance were identified. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of CCM2 in the families reported by Liquori et al. (2003) was consistent with autosomal dominant inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>Liquori et al. (2003) sequenced positional candidate genes in the 7p region for mutations in CCM2. One of these genes, the CCM2 gene, which they called MGC4607, was chosen because its translation product protein encodes a putative phosphotyrosine-binding (PTB) domain. The same domain is found in ICAP1-alpha (607153), a binding partner of the KRIT1 gene (604214). In a panel of 27 probands without a KRIT1 mutation, Liquori et al. (2003) detected 8 different heterozygous mutations in the CCM2 gene (see, e.g., 607929.0001-607929.0004). </p><p>In 2 (14%) of 14 unrelated patients with sporadic CCM and multiple lesions, Felbor et al. (2007) identified a respective deletion in the CCM2 gene using multiplex ligation-dependent probe amplification. One of the deletions involved the entire coding region of the CCM2 gene. </p><p>In 8 (13%) of 63 U.S. families with CCM, Liquori et al. (2007) identified a 77.6-kb deletion encompassing exons 2 through 10 in the CCM2 gene (607929.0009). </p><p>Liquori et al. (2008) reported 6 additional CCM families from the United States with the 77.6-kb CCM2 deletion. Haplotype analysis, which included the previously reported families with this deletion, indicated a founder effect. This deletion was not present in 24 Italian families with CCM, indicating that it is specific to a certain cohort of patients. Among the 24 Italian families with CCM, Liquori et al. (2008) identified 4 deletions and 1 duplication in the CCM2 gene. </p><p>By use of repeated cycles of amplification, subcloning, and sequencing of multiple clones per amplicon, Akers et al. (2009) identified somatic mutations that were otherwise invisible by direct sequencing of the bulk amplicon. Biallelic germline and somatic mutations were identified in CCM lesions from all 3 forms of inherited CCMs. The somatic mutations were found only in a subset of the endothelial cells lining the cavernous vessels and not in interstitial lesion cells. Although widely expressed in the different cell types of the brain, the authors also suggested a unique role for the CCM proteins in endothelial cell biology. Akers et al. (2009) suggested that CCM lesion genesis may require complete loss of function for one of the CCM genes. </p><p>Gallione et al. (2011) identified a founder mutation in the Ashkenazi Jewish population that affects mRNA splicing of the CCM2 gene causing cerebral cavernous malformations (607929.0010). </p><p>In 27 unrelated patients with CCM and heterozygosity for the 77.6-kb deletion (607929.0009) encompassing exons 2-10 of the CCM2 gene, Gallione et al. (2022) sequenced 10 kb upstream and downstream of the deletion to evaluate for a shared haplotype. SNP analysis demonstrated a shared haplotype among all 27 patients. The deletion was shown to be due to a recombination between an AluSx and an AluSg sequence, which, although highly homologous, are not identical. Genealogy studies showed that 5 of the families may share a single common ancestor. </p><p>Bergametti et al. (2020) identified 6 heterozygous mutations in the CCM2 gene (607929.0007; 607929.0011-607929.0015) in 7 unrelated patients with CCM. The mutations were identified by sequencing of 3 genes associated with cerebral cavernous malformations. Coimmunoprecipitation studies with each of the mutations resulted in loss of interaction between CCM1 and CCM2. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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Ahdab, R., Riant, F., Brugieres, P., Roujeau, J.-C., Hodel, J., Hosseini, H.
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<strong>Familial cerebral cavernomatous malformations associated with palmar capillary telangiectasias.</strong>
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Neurology 71: 861-862, 2008.
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[Full Text: https://doi.org/10.1212/01.wnl.0000325474.61048.ae]
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</li>
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Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A.
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<strong>Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.</strong>
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Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F.
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<strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong>
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J. Med. Genet. 57: 400-404, 2020.
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Craig, H. D., Gunel, M., Cepeda, O., Johnson, E. W., Ptacek, L., Steinberg, G. K., Ogilvy, C. S., Berg, M. J., Crawford, S. C., Scott, R. M., Steichen-Gersdorf, E., Sabroe, R., Kennedy, C. T. C., Mettler, G., Beis, M. J., Fryer, A., Awad, I. A., Lifton, R. P.
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<strong>Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27.</strong>
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Hum. Molec. Genet. 7: 1851-1858, 1998.
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Denier, C., Goutagny, S., Labauge, P., Krivosic, V., Arnoult, M., Cousin, A., Benabid, A. L., Comoy, J., Frerebeau, P., Gilbert, B., Houtteville, J. P., Jan, M., and 14 others.
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<strong>Mutations within the MGC4607 gene cause cerebral cavernous malformations.</strong>
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Am. J. Hum. Genet. 74: 326-337, 2004.
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Felbor, U., Gaetzner, S., Verlaan, D. J., Vijzelaar, R., Rouleau, G. A., Siegel, A. M.
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<strong>Large germline deletions and duplication in isolated cerebral cavernous malformation patients.</strong>
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Neurogenetics 8: 149-153, 2007.
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[Full Text: https://doi.org/10.1007/s10048-006-0076-7]
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Gallione, C. J., Detter, M. R., Sheline, A., Christmas, H. M., Lee, C., Marchuk, D. A.
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<strong>Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene.</strong>
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Hum. Genet. 141: 1761-1769, 2022.
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[PubMed: 35488064]
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[Full Text: https://doi.org/10.1007/s00439-022-02458-5]
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Gallione, C. J., Solatycki, A., Awad, I. A., Weber, J. L., Marchuk, D. A.
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<strong>A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.</strong>
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Genet. Med. 13: 662-666, 2011.
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[PubMed: 21543988]
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[Full Text: https://doi.org/10.1097/GIM.0b013e318211ff8b]
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Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A.
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<strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong>
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Am. J. Hum. Genet. 73: 1459-1464, 2003.
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[PubMed: 14624391]
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[Full Text: https://doi.org/10.1086/380314]
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Liquori, C. L., Berg, M. J., Squitieri, F., Leedom, T. P., Ptacek, L., Johnson, E. W., Marchuk, D. A.
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<strong>Deletions in CCM2 are a common cause of cervical cavernous malformations.</strong>
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Am. J. Hum. Genet. 80: 69-75, 2007.
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[PubMed: 17160895]
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[Full Text: https://doi.org/10.1086/510439]
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Liquori, C. L., Penco, S., Gault, J., Leedom, T. P., Tassi, L., Esposito, T., Awad, I. A., Frati, L., Johnson, E. W., Squitieri, F., Marchuk, D. A., Gianfrancesco, F.
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<strong>Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts.</strong>
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Neurogenetics 9: 25-31, 2008.
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[PubMed: 18060436]
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[Full Text: https://doi.org/10.1007/s10048-007-0109-x]
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Pagenstecher, A., Stahl, S., Sure, U., Felbor, U.
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<strong>A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.</strong>
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Hum. Molec. Genet. 18: 911-918, 2009.
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[PubMed: 19088124]
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[Full Text: https://doi.org/10.1093/hmg/ddn420]
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Hilary J. Vernon - updated : 08/04/2023<br>Ada Hamosh - updated : 8/19/2011<br>George E. Tiller - updated : 8/26/2009<br>Cassandra L. Kniffin - updated : 3/23/2009<br>Cassandra L. Kniffin - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 5/4/2007<br>Victor A. McKusick - updated : 12/18/2003
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